1. Field of the Invention
The invention pertains to a method and apparatus for monitoring organ metabolism and is illustrated by method and apparatus directed to monitoring cellular oxidative metabolism by conducting non-invasive, in vivo, in situ measurements of changes in the steady state oxidation-reduction of cellular cytochromes together with changes in blood volume, the oxygenation state of hemoglobin and the rate of blood flow in the brain, heart, kidney, other organs, in limbs or other parts of a human or animal body.
2. History of the Prior Art
It is generally known that metabolism and more particularly oxygen sufficiency and adequacy of utilization are parameters of fundamental importance in assessing the function of any body organ. This is made self-evident when one considers that the energy provision for tissue function is underwritten for better than 94 percent by oxidative reactions involving the reduction of O.sub.2 to H.sub.2 O. In the absence of sufficient oxygen, this process becomes impaired with a corresponding impairment in organ function. In instances of extensive oxygen deprivation, over a period of time the organ loses viability and as a result the individual often has the same fate.
Although all organs are adversely affected by oxygen insufficiency, perhaps the problem is most acute in the case of the brain because of its exquisite sensitivity with respect to oxygen demand and its complete dependence on oxidative metabolism for proper function and viability. For example, an absence of oxygen in the brain for more than a dozen seconds produces dysfunction and an absence for longer than a few minutes spells irreversible damage. A less acute impairment of oxygen availability leads to a gradual loss in brain function, especially with respect to the higher centers of the cerebral cortex.
Because of the vital role that oxygen sufficiency plays in human physiology, intensive efforts have been made over the years to measure this parameter in various organs and most particularly in connection with the assessment of brain and heart function. However, a capability for direct measurement of the parameter in the intact brain, heart or any other organ by a non-invasive means has not previously been available. The prior methods have all been of a secondary nature (e.g., electroencephalographic changes during hypoxia) or indirect and traumatic (e.g., blood flow measurements).
At present, electroencephalograph recordings indicating dysfunction are mainly useful for diagnosis of severely hypoxic or anoxic conditions in the brain. Similarly, electrocardiograph recordings are used to establish an oxygen deficiency in the heart muscle. However, such methods are diagnostic only in far-advanced situations and the organ and patient are both in a precarious state before these signals become indicative of pathology.
Measurements of cerebral blood flow and more recently of myocardial blood flow are predicated on the assumption that insufficient circulation is the main cause of inadequacy of oxygen delivery to the tissues. Although this assumption is probably correct in the majority of cases, the fact remains that the method is indirect, beclouded by possibilities of arterial-venous (A-V) shunting and unable to distinguish inadequate micro-regional bloodflow especially when accompanied by macro-regional changes.
Local blood flow measurement is presently accomplished by means of radioactive materials incorporated in the blood supplying the organ in question during monitoring of local radioactivity of the patient. Administration is either by inhalation of a radioactive isotope of a gas or by arterial or venous injection of a solution containing such a gas. The gas must have sufficient solubility to be easily dissolved in the blood and tissues and its isotope must have sufficiently strong radiation to penetrate the overlying tissue to be externally monitored. Commonly, .sup.133 Xenon is employed for this purpose.
The method most commonly used is the wash-out technique after a bolus of .sup.133 Xenon containing solution is administered intraarterially or after breathing a gas mixture containing .sup.133 Xenon until a certain degree of saturation of the cerebral tissue has been accomplished. Blood flowing into the lungs will rapidly eliminate the .sup.133 Xenon from the blood, arterial levels will drop precipitously and from thereon the tissue .sup.133 Xenon levels will be washed out by equilibration with Xenon-free arterial blood. The rate of this process is mainly determined by the rate of blood flow through the observed area. Usually, several compartments with different time courses will be observed, the first being the blood itself, others being various fractions of tissue with different circulatory parameters. From these wash-out curves, which take many minutes to be completed, the rate of blood flow in the tissue (or tissues) is then calculated. Deductions about possible circulatory deficiencies are made and translated into further deductions concerning possible deficiencies of oxygen delivery to the tissue. Aside from the indirect nature of the information obtained, serious drawbacks exist in the need to expose the patient to radioactivity.
In yet another procedure, the arterial-venous (A-V) difference technique has been used in efforts to assess the uptake of oxygen across intact organs. This method depends on measuring the difference between oxygen concentration in the arterial blood supplying the tissue and the venous blood returning from it.
When used in brain studies, for example, a sample of arterial blood is drawn from a peripheral artery and a sample of venous blood returning from the head is obtained by means of a hypodermic needle which is inserted into the jugular bulb of the neck. Also, in order to calculate the rate of oxygen uptake, the total rate of blood flow must be measured. Aside from the fact that the measurement is contaminated with oxygen uptake from structures of the head other than the brain, the method is traumatic and incurs a degree of risk by the need for penetrating the jugular bulb. Moreover, measurements on myocardial oxygen uptake are precluded since pure venous blood from the heart muscle cannot be obtained routinely.
Oximetry techniques have been widely employed for monitoring the arterial blood oxygenation in general. However, such techniques are not directed to providing information primarily concerned with organ or cellular metabolism and more specifically with oxidative metabolism. While oximeter constructions and techniques employed in oximetry are believed to be widely known among those skilled in the art, reference to the same may be found in the book "A MANUAL OF REFLECTION OXIMETRY", W. G. Zijlstra, M.D., 1958, Koninklijke Van Gorcum & Comp. N.V., Assen, Netherlands. A useful background in the literature can be found in the following articles:
(1) Review of Scientific Instruments, Vol. 13, pgs. 434-444, 1942;
(2) Principles of Applied Biomedical Instrumentation, L. A. Geddes & L. E. Baker, pgs. 85-91, 1968; (3) Journal of Applied Physiology, 17: pgs. 552-558, 1962; (4) Journal of Laboratory and Clinical Medicine, 34: pgs. 387-401, 1949; (5) Annals of Surgery, 130: pgs. 755-773, 1949.
Transillumination of tissues by a laser beam of visible or near visible light at a low, non-hazardous power level not sufficiently intense to cause a reaction of the tissue is discussed in U.S. Pat. No. 3,769,963. Also, this patent illustrates in FIG. 1 of the patent use of such a non-hazardous light source as a probe for transillumination over what would appear to be a relatively long optical path possibly including both bone and tissue. Transillumination with an intense, incoherent light source as a diagnostic procedure is described on page 373 of the book "LASERS IN MEDICINE", Leon Goldman, M.D. and R. James Rockwell, Jr., 1971, Gordon and Breach, Science Publishers, Inc. New York, New York. The chapter of this book entitled "Laser Biology" also provides useful background. Laser transillumination as a diagnostic technique is also discussed at page 130 of the book "BIOMEDICAL ASPECTS OF THE LASER", Leon Goldman, M.D., 1967, Springer-Verlag New York Inc. What can be seen from these references is that transillumination over relatively long optical paths including bone and tissue can be achieved. However, none of such references are directed to the objectives or achievements of the present invention, namely that of using a relatively non-intense, relatively low power level, coherent light source within the near infrared region as a non-invasive means and method of continuously measuring body organ metabolism in vivo, in situ and atraumatically.
Circuitry for establishing periodically recurring reference and measuring light pulses and for measuring the transmitted, in vitro difference or intensity therebetween is illustrated in U.S. Pat. Nos. 3,799,672 and 3,804,535. Also, U.S. Pat. No. 3,804,535 teaches a type of feedback to the photomultiplier voltage supply as does U.S. Pat. No. 3,923,403. Mention of such feedback is made because the circuitry of the present invention utilizes a unique type of feedback in an in vivo, in situ, transillumination system to compensate for and monitor the blood volume changes in measurements of organ oxidative metabolism as compared to the reflectance-transillumination systems of the prior art described in the mentioned prior art which operate in vitro and generally produce no information related to in vivo, in situ oxidative metabolism as with the present invention.
Note should also be made with reference to U.S. Pat. No. 3,804,535 to the fact that employment of a reference signal related to an isobestic point, i.e., at which absorbance of oxygenated and deoxygenated (or "disoxygenated") blood are equal, has been known as a technique for revealing absorption characteristics of a measuring signal at another wavelength. However, this technique has not heretofore been employed as a means for compensating for blood volume changes in an in vivo, in situ transillumination system designed to measure cellular and organ oxidative metabolism.
A further aspect of the prior art to be appreciated is the application of the so-called Beer-Lambert Law for determining optical density by determining circuit parameters from the two conditions, namely of the light being transmitted directly without passing through the test subject as compared to the light being transmitted through the test subject. Various literature sources discuss how this law is applied, one such source being the above-mentioned U.S. Pat. No. 3,923,403.
An appreciation of how various combinations of measuring and reference wavelengths have been applied in the prior art for physiological measurements is also deemed useful to an appreciation of the present invention. In this regard, U.S. Pat. Nos. 3,704,706; 3,709,672; 3,804,535; 3,807,390; 3,831,030 and 3,910,701 may be referred to for background examples of various singular and multiple wavelength combinations, some of which reside within the near infrared region of interest to the present invention. However, what can be noted with reference to all such prior art is that none of the methods or circuitry apparatus therein disclosed provide means for in vivo, in situ monitoring of metabolism and more specifically of cellular oxidative metabolism of an internal organ as with the present invention.
Thus, it becomes apparent that while circulatory-respiratory functions, arterial blood oxygenation and blood samples, per se, have been monitored by photometric techniques, presently existing method and apparatus are not suited for assessing the sufficiency of oxygen and metabolism in general in such vital organs as the brain and heart. Further, such prior methods and apparatus do not provide precise information and are often traumatic as well. Consequently, an obvious need exists for a method and apparatus by which this life sustaining parameter, i.e., cellular oxidative metabolism, can be measured in vivo, in situ and monitored continuously with precision and in a non-invasive, non-traumatic manner. Equally important is a need to be able to monitor blood volume and blood flow rate of the organ being monitored.